Carboxylesterase expression in human dental pulp cells: role in regulation of BisGMA-induced prostanoid production and cytotoxicity

Biocompatibility of dentin bonding agents (DBA) and composite resin may affect the treatment outcome (e.g., healthy pulp, pulpal inflammation, pulp necrosis) after operative restoration. Bisphenol-glycidyl methacrylate (BisGMA) is one of the major monomers present in DBA and resin. Prior studies focused on salivary esterase for metabolism and degradation of resin monomers clinically. This study found that human dental pulp cells expressed mainly carboxylesterase-2 (CES2) and smaller amounts of CES1A1 and CES3 isoforms. Exposure to BisGMA stimulated CES isoforms expression of pulp cells, and this event was inhibited by catalase. Exogenous addition of porcine esterase prevented BisGMA- and DBA-induced cytotoxicity. Interestingly, inhibition of CES by bis(p-nitrophenyl) phosphate (BNPP) and CES2 by loperamide enhanced the cytotoxicity of BisGMA and DBA. Addition of porcine esterase or N-acetyl-l-cysteine prevented BisGMA-induced prostaglandin E(2) (PGE(2)) and PGF(2α) production. In contrast, addition of BNPP and loperamide, but not mevastatin, enhanced BisGMA-induced PGE(2) and PGF(2α) production in dental pulp cells. These results suggest that BisGMA may induce the cytotoxicity and prostanoid production of pulp cells, leading to pulpal inflammation or necrosis via reactive oxygen species production. Expression of CES, especially CES2, in dental pulp cells can be an adaptive response to protect dental pulp against BisGMA-induced cytotoxicity and prostanoid release. Resin monomers are the main toxic components in DBA, and the ester group is crucial for monomer toxicity.     

Androgen Receptor Influences on Body Defense System via Modulation of Innate and Adaptive Immune Systems: Lessons from Conditional AR Knockout Mice

Upon insult, such as infection or tissue injury, the innate and adaptive immune systems initiate a series of responses to defend the body. Recent studies from immune cell-specific androgen receptor (AR) knockout mice demonstrated that androgen and its receptor (androgen/AR) play significant roles in both immune regulations. In the innate immunity, androgen/AR is required for generation and proper function of neutrophils; androgen/AR also regulates wound healing processes through macrophage recruitment and proinflammatory cytokine production. In adaptive immunity, androgen/AR exerts suppressive effects on development and activation of T and B cells. Removal of such suppression causes thymic enlargement and excessive export of immature B cells. Altogether, androgen/AR plays distinct roles in individual immune cells, and targeting androgen/AR may help in treatment and management of immune-related diseases.The immune system includes both innate and adaptive immune responses. Once insult to the body (eg, infection) is initially encountered, the innate system acts within minutes, followed some hours later by early induced responses conducted by recruited effector cells, such as neutrophils and macrophages, in a nonspecific manner.^1,2 In most cases, infections are eliminated by the innate immune system. When pathogens breach the first line of immune defense, however, the adaptive immune system is activated with antigen-specific effectors (eg, T and B cells), and the generation of memory cells ensures a long-lasting and prompt response to recurrent infection with the same pathogens. On the other hand, the context of the activated innate immunity also shapes the outcome of adaptive immune responses.³Androgen and androgen receptor (AR) signals control the development and function of both male and female reproductive systems.^4–6 The AR gene is located on the X chromosome in both the human and the murine genome. AR is a prototypical nuclear receptor, containing an N-terminal domain, a ligand-binding domain, a DNA-binding domain, and a C-terminal domain.⁷ After binding of its ligands, testosterone or 5α-dihydrotestosterone, AR translocates into the nucleus and binds to androgen responsive elements on the promoters or enhancers of target genes, thereby turning on their expression.⁸ The expression of AR has been detected in various immune cell lineages, including neutrophils, mast cells, macrophages, B cells, and T cells,^9–11 implying the involvement of androgen and its receptor (androgen/AR) in regulating the development and function of the immune system.It has long been suspected that, in both animals and humans, the male sex hormones may modulate the development and function of the immune system. Males are at higher risk of developing sepsis, acute respiratory distress, and multiorgan failure after soft-tissue traumatic hemorrhagic shock and thermal injury, in part because of immune suppression and abnormal activation of neutrophils.¹² On the other hand, males are less prone to autoimmune diseases. Of more than 70 chronic disorders categorized as autoimmune diseases, many affect predominantly women.^13,14 Various studies have uncovered important immune regulatory functions of androgen/AR (as discussed below), and such nonclassical roles of androgen/AR outside the reproductive system are important for understanding the pathogenesis of these immunological conditions.Recent studies using conditional AR knockout (ARKO) mice, with knockout of AR in selective immune cells, opened a new era for investigating the nonclassical roles of androgen/AR involved in immune regulation; these studies also suggest potential for the development of new therapeutic strategies for treating immune-related diseases.^6,15 In this review, we summarize the roles of androgen/AR in both the innate and adaptive components of the immune system (specifically neutrophils, macrophages, T cells, and B cells), as well as new evidence from studies using conditional ARKO mice. We also address the potential influences of androgen/AR on immune-related diseases.     

卡维地洛联合坎地沙坦对心力衰竭患者血浆N末端B型利钠肽原浓度的影响

目的：观察卡维地洛联合坎地沙坦对心力衰竭（CHF）患者血浆N末端B型利钠肽原（NT-proBNP）浓度的影响。方法：将175例CHF患者随机分为对照组（常规治疗）和治疗组（卡维地洛联合坎地沙坦治疗）。分别于用药前及用药3个月后测定血浆NT-proBNP浓度、左心室射血分数（LVEF）、左室短轴缩短率（FS）及心脏指数（CI）。结果：治疗组总有效率为87.5%,对照组总有效率为70.1%,治疗组较对照组明显提高（P〈0.01）,两组治疗后的LVEF、FS、CI、血浆NT-proBNP浓度明显改善（治疗组t=23.167、14.041、6.602、60.735,均P〈0.01;对照组t=4.943、4.698、3.73、48.673,均P〈0.05）;治疗后治疗组LVEF、FS、CI较对照组改善显著（t=15.948、6.822、5.88,均P〈0.01）,血浆NT-proB-NP浓度明显降低（t=14.794,P〈0.01）。结论：卡维地洛联合坎地沙坦可改善CHF患者心功能,降低血浆NT-proBNP浓度,对治疗心力衰竭安全有效。     

Growing your own: community health workers and jobs to careers

This article evaluates the implementation and impact of 5 workforce development programs aimed at achieving skills upgrades, educational advancement, and career development for community health workers (CHWs). Quantitative and qualitative case study data from the national evaluation of the Jobs to Careers: Transforming the Front Lines of Health Care initiative demonstrate that investing in CHWs can achieve measurable worker (eg, raises) and programmatic (eg, more skilled workers) outcomes. To achieve these outcomes, targeted changes were made to the structure, culture, and work processes of employing organizations. These findings have implications for other health care employers interested in developing their CHW workforce.     

The synthesized novel fluorinated compound (LJJ-10) induces death receptor- and mitochondria-dependent apoptotic cell death in the human osteogenic sarcoma U-2 OS cells

We designed the 6-fluoro-2-(3-fluorophenyl)-4-substituted anilinoquinazoline derivatives as less toxic anti-cancer candidates. Our result demonstrated that LJJ-10 has greater cytotoxicity than that of the other compounds in human osteogenic sarcoma U-2 OS cells. LJJ-10-induced apoptosis was associated with enhancing ROS generation, DNA damage, and an increase of the protein levels of Fas, FasL, FADD, caspase-8, cytochrome c, Apaf-1, AIF, Endo G, caspase-9 and caspase-3 in U-2 OS cells. LJJ-10-triggered growth inhibition was significantly attenuated by N-acetylcysteine, cyclosporine A, anti-FasL monoclonal antibody, and caspase-8, -9 and -3 specific inhibitors in U-2 OS cells. We suggest that LJJ-10-induced apoptotic cell death in U-2 OS cells through death receptor- and mitochondria-dependent apoptotic signaling pathways.     

中国残疾人群现状与预防研究进展

残疾是指由于疾病、意外伤害等各种原因所致的人体解剖结构、生理功能的异常和/或丧失,从而导致部分或全部丧失正常人生活、工作和学习的能力,无法负担其日常生活和社会职能.残疾,特别是严重功能残障的残疾,对个人、家庭和社会都会产生不利的影响,导致巨大的社会和经济负担.世界卫生组织(WHO)指出,利用现有的技术可以使至少50%的残疾得以控制或使其延迟发生[1].因此,了解我国残疾人群现状和残疾预防研究的进展,积极开展残疾预防工作,减少残疾人口的增长是我国政府和相关部门刻不容缓的任务.本文就我国目前的残疾现状与残疾预防研究进展做一综述.     

Chicken HSP70 DNA vaccine inhibits tumor growth in a canine cancer model

Immunization with xenogeneic DNA is a promising cancer treatment to overcome tolerance to self-antigens. Heat shock protein 70 (HSP70) is over-expressed in various kinds of tumors and is believed to be involved in tumor progression. This study tested a xenogeneic chicken HSP70 (chHSP70) DNA vaccine in an experimental canine transmissible venereal tumor (CTVT) model. Three vaccination strategies were compared: the first (PE) was designed to evaluate the prophylactic efficacy of chHSP70 DNA vaccination by delivering the vaccine before tumor inoculation in a prime boost setting, the second (T) was designed to evaluate the therapeutic efficacy of the same prime boost vaccine by vaccinating the dogs after tumor inoculation; the third (PT) was similar to the first strategy (PE), with the exception that the electroporation booster injection was replaced with a transdermal needle-free injection. Tumor growth was notably inhibited only in the PE dogs, in which the vaccination program triggered tumor regression significantly sooner than in control dogs (NT). The CD4⁺ subpopulation of tumor-infiltrating lymphocytes and canine HSP70 (caHSP70)-specific IFN-γ-secreting lymphocytes were significantly increased during tumor regression in the PE dogs as compared to control dogs, demonstrating that specific tolerance to caHSP70 has been overcome. In contrast, no benefit of the therapeutic strategy (T) could be noticed and the (PT) strategy only led to partial control of tumor growth. In summary, antitumor prophylactic activity was demonstrated using the chHSP70 DNA vaccine including a boost via electroporation. Our data stressed the importance of DNA electroporation as a booster to get the full benefit of DNA vaccination but also of cancer immunotherapy initiation as early as possible. Xenogeneic chHSP70 DNA vaccination including an electroporation boost is a potential vaccine to HSP70-expressing tumors, although further research is still required to better understand true clinical potential.